The development of neoplasms in vertebrates is often associated with alterations in the structure or expression of cellular proto-oncogenes. We have been characterizing the cbl proto-oncogene which was first discovered in a defecteve retrovirus that induces pre-B lymphomas in vivo. The sequences of 4 cDNA clones (2 human and 2 mouse) suggest that cbl may be a transcription factor. There is homology with the GCN4 transcriptional activation region, a proline rich region, a basic region and a leucine zipper. One of the murine cDNAs, however, differs completely at its 3' end in that it is lacking the leucine zipper motif and would encode a shorter protein. There are no nucleotide differences between v-cbl and c-cbl, rather, v-cbl is a truncated form of the gene which also does not contain the leucine zipper. Sequencing of the germline locus has identified 7 exons so far, ranging in size from 120 to 201bp. Cbl is not an immediate early gene and its expression is not regulated upon the addiiton of mitogens to various cell types. Cbl, however may play a role in the differentiation of certain cell types since terminal differentiation of an erythroid and of a promyelocytic cell line shuts off cbl expression. NIH3T3 cells have been transfected with various cbl constructs. A construct with c-cbl is weakly transforming while a construct with v-cbl is only slightly better at transforming these cells. The construct containing the c-cbl lacking the leucine zipper did not transform cells at all. Transgenic mice have been developed containing constructs with either v-cbl or c-cbl in conjunciton with the IgH enhancer. To date, the c-cbl transgenic mice have not developed tumors but spleens from two mice did not show elevated levels of cbl expression. Transgenic mice containing v-cbl are in the process of being bred for further studies.